JPH08291194A - Ginseng sapogenin and its production - Google Patents

Abstract

PURPOSE: To obtain a new sapogenin for enhancing agents, etc., capable of increasing sensitivity of cancer to antitumor agent by carrying out hydrolysis and dehydrogenation treatment of glycoside containing 20 (S)-protopanaxadiol and trial extracted from ginseng as a skeleton. CONSTITUTION: This compound is a new dammara-20(22),24-diene-3β, 12β-diol expressed by formula I or a new dammara-20(22),24-diene-3β,6α, 12β-triol expressed by formula II. The compound is extremely useful as a enhancing agent capable of remarkably enhancing chemotherapeutic effect of an antitumor agent by increasing sensitivity of a cancer cell which acquired multiple drug resistance to the antitumor agent and cancelling multiple drug resistance. The compound can be obtained as a sapogenin by carrying out hydrolysis and dehydration treatment of glycoside containing 20 (S)-protopanaxadiol and triol extracted from ginseng (e.g. Panax ginsing) as a skeleton.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carrot sapogenin, a method for producing the same, and an enhancer for increasing the susceptibility of cancer to an anticancer agent containing the new carrot sapogenin as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Complete cure of various cancers such as leukemias, lymphomas, and solid cancers by the use of chemotherapeutic agents is rare because of the uneven sensitivity of cancer cells to each anticancer drug.
Chemotherapy for cancer also fails due to the intrinsic resistance to multidrug treatment of cancer. In other cases, the cancer may become resistant to anti-cancer drugs used in previous treatments.
At that time, the therapeutic effects of these drugs are eliminated. An even more important issue is that recurrent cancers are not only resistant to anti-cancer drugs used in previous treatments, but also unrelated to previously used drugs, either by chemical structure or mechanism of action. It may also show resistance to the anti-cancer drug. Collectively, these phenomena are called multidrug resistance and are widely involved in clinical cancer treatment.

[0003]

[Problems to be Solved] Under the present circumstances of such cancer chemotherapy, a drug that enhances the efficacy of an anticancer drug in order to overcome multidrug resistance and reduce side effects of the anticancer drug such as myelosuppression It is urgent to develop. A typical drug used for this purpose is verapamil [Tsuruo, T .; Cancer Res. 41, 1967 (1981)].
And cyclosporin A [Slater, L .; J. Clin. Invest.
77, 1405 (1986)], but clinical application is said to be difficult due to side effects. The inventors of the present invention separated the crude saponin of medicinal carrot from the degradation product obtained by hydrolysis and dehydration reaction in the process of searching for a drug that enhances the drug efficacy of an anticancer drug, and then isolated it from wadipanaxadiol and wadipa It was found that a novel carrot sapogenin, named naxatriol, of unknown structure eliminates multidrug resistance by increasing the susceptibility of cancer to anticancer drugs and significantly enhances the chemotherapeutic effect of anticancer drugs. Therefore,
Since a chemical structure of carrot sapogenin of unknown structure was determined and a method capable of industrially producing the carrot sapogenin was invented, the present invention was completed together with the action of enhancing the drug efficacy of these anticancer agents.

[0004]

That is, the present invention provides:
Formula (I), a new carrot sapogenin:

The quasipanaxadiol represented by the formula
Damara-20 (22), 24-diene-3 named anaxadiol)
β, 12β-diol (dammara-20 (22), 24-diene-3β, 12β
-diol), and this sapogenin has the following features. 1) The melting point is 150-153 ° C. 2) It has an optical rotation of [α] _D ²⁰ + 15 ° (C = 1.0, methanol). 3) It has a molecular composition of C ₃₀ H ₅₀ O ₂ . 4) Infrared absorption spectrum (KBr, cm ^-1 ) is 3400,290
It has the absorption maximum peculiar to 0, 1450, 1380, and 1020. 5) Mass spectrum (Fab, m / z) shows 441 (MH) ⁻ . 7) ¹³ C nuclear magnetic resonance spectrum (d ₅ -pyridine) shows 39.3
(C-1), 27.0 (C-2), 78.5 (C-3), 40.4 (C-4), 56.4 (C-5),
18.5 (C-6), 35.3 (C-7), 37.1 (C-8), 50.9 (C-9), 39.6
(C-10), 32.2 (C-11), 71.9 (C-12), 50.4 (C-13), 51.2 (C
-14), 32.6 (C-15), 26.8 (C-16), 51.2 (C-17), 16.8 (C-1
8), 16.5 (C-19), 140.2 (C-20), 27.4 (C-21), 123.8 (C-2
2), 30.0 (C-23), 125.4 (C-24), 131.5 (C-25), 25.7 (C-2
6), 17.7 (C-27), 28.2 (C-28), 15.8 (C-29), 17.0 (C-30)
Signal of. 8) Odorless, colorless needle crystals (crystallized from methanol-water). 9) Easily soluble in methanol, ethanol, n-butanol, 2-propanol, n-propanol, pyridine, dimethylsulfoxide, ethyl acetate, ether and acetone, and soluble in chloroform, methylene chloride, benzene, hexane and petroleum ether. 10) In thin layer chromatography (TLC, carrier: precoated silica gel 70F254, 0.2 mm, manufactured by Wako Co .; developing solvent: chloroform-ethyl acetate-ethanol (10: 2: 0.007)), R
An f value of 0.55 is shown. Further, Rf value 0.41 is shown in thin layer chromatography (TLC, carrier: reverse phase pre-coated silica gel RP-8F254s, manufactured by Merck; developing solvent: 95% methanol). T
Spray 10% aqueous sulfuric acid on LC and heat to give magenta to brown.

The present invention also provides a novel carrot sapogenin of formula (II):

The quasi-panaxatriol represented by the formula
Damara named ipanaxatriol) -20, (22), 24-diene
-3β, 6α, 12β-triol (dammara-20 (22), 24-diene-
3β, 6α, 12β-triol), and this sapogenin has the following features. 1) The melting point is 165-168 ° C. 2) It has an optical rotation of [α] _D ²⁰ + 50 ° (C = 1.0, methanol). 3) It has a molecular composition of C ₃₀ H ₅₀ O ₃ . 4) Infrared absorption spectrum (KBr, cm ^-1 ) is 3450,296
It has the absorption maximum peculiar to 0, 1435, 1390, and 1050. 5) Mass spectrum (Fab, m / z) shows 457 (MH) ⁻ . 7) ¹³ C nuclear magnetic resonance spectrum (d ₅ -pyridine) shows 39.6
(C-1), 28.2 (C-2), 78.5 (C-3), 40.4 (C-4), 61.9 (C-
5), 67.8 (C-6), 47.8 (C-7), 41.5 (C-8), 50.6 (C-9), 39.
6 (C-10), 28.9 (C-11), 72.7 (C-12), 50.8 (C-13), 50.9
(C-14), 32.3 (C-15), 28.2 (C-16), 50.5 (C-17), 17.7 (C
-18), 17.5 (C-19), 140.2 (C-20), 13.2 (C-21), 123.6 (C
-22), 27.5 (C-23), 123.9 (C-24), 135.3 (C-25), 25.7 (C
-26), 17.7 (C-27), 32.0 (C-28), 16.5 (C-29), 17.2 (C-3
0) signal is shown. 8) Odorless, colorless needle crystals (crystallized from methanol-water). 9) Easily soluble in methanol, ethanol, n-butanol, 2-propanol, n-propanol, pyridine, dimethylsulfoxide, ethyl acetate, ether and acetone, and soluble in chloroform, methylene chloride, benzene, hexane and petroleum ether. 10) In thin layer chromatography (TLC, carrier: precoated silica gel 70F254, 0.2 mm, manufactured by Wako Co .; developing solvent: chloroform-ethyl acetate-ethanol (1: 1: 0.015)), Rf
A value of 0.45 is shown. Further, it shows an Rf value of 0.31 in thin layer chromatography (TLC, carrier: reverse-phase precoated silica gel RP-8F254s, manufactured by Merck & Co .; developing solvent: 85% methanol). T
Spray 10% aqueous sulfuric acid on LC and heat to give magenta to brown.

Further, the present invention provides a mulberry obtained as sapogenin by subjecting a glycoside having 20 (S) -protopanaxadiol and 20 (S) -protopanaxatriol as a skeleton to hydrolysis and dehydration. It provides a process for making dipanaxadiol (Formula I) and quazipanaxatriol (Formula II), which is described in detail below. That is, in the method of the present invention, the above-ground part and the underground part of medicinal carrot, particularly Panax ginseng, S.A. Meyer, and its tissue culture are extracted with a solvent, and 20 (S) -protopanaxazide is used. A mixture of all and 20 (S) -protopanaxatriol skeleton glycosides (ginsenoside) (hereinafter referred to as total ginsenoside)
Is separated and subjected to hydrolysis and dehydration treatments to produce wadipanaxadiol and wadipanaxatriol, which are the objects of the present invention. In the method of the present invention, first, post-degreasing treatment extraction is performed without degreasing the raw medicinal carrot or using a normal fat-soluble organic solvent such as n-hexane. a) The raw material is cold-soaked in a lower alcohol such as methanol or ethanol, heated if necessary, and filtered to obtain an extract. This extraction operation may be repeated if necessary. These extracts are combined and the solvent is distilled off under reduced pressure to obtain an extract. This extract was partitioned between n-hexane and water, the aqueous layer was further extracted with ether as necessary, the aqueous layer was extracted with n-butanol, and the solvent for the n-butanol was removed under reduced pressure. The solvent is distilled off, and total ginsenoside is obtained as an n-butanol extract. b) The raw material is cold-soaked in a lower alcohol such as methanol or ethanol, heated if necessary, and filtered to obtain an extract. This extraction operation may be repeated if necessary. These extracts are combined and the solvent is distilled off under reduced pressure to obtain an extract. This extract is distributed between n-hexane and water, the aqueous layer is further extracted with ether as necessary, and the aqueous layer is adsorbed on a porous cross-linked polystyrene resin with a giant network structure (for example, Diaion HP-20,
(Made by Mitsubishi Kasei Co., etc.). These adsorbents are
It is used in an amount of 5 to 10 times the amount of contained saponin. Then, the resin is thoroughly washed with water, eluted with a lower alcohol such as methanol or ethanol, or water containing about 30% or more lower alcohol, and concentrated to obtain total ginsenoside.

[0007] The total ginsenoside obtained by the above method contains various carrot saponins, and the target substances wadipanaxadiol and wadipanaxatriol are produced by the following method. a) Dissolve total ginsenoside in water, add crude hesperidinase or a glycolytic enzyme such as that derived from human intestinal bacteria, and stir to react at about 36 to 37 ° C for 1 to 2 days. The sugar bound to the glucose group at the position is removed by an enzymatic hydrolysis reaction. A precipitate forms when the sugar is removed. Then, by adding an equivalent amount of acetic acid to the reaction solution and heating, or by adding concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid so that the concentration becomes 0.1 N, or adding trifluoroacetic acid so that the concentration becomes 0.5%, and heating at room temperature or The hydroxyl group bonded to the 20th position is removed by a dehydration reaction. b) Dissolve total ginsenoside in water, lower alcohol or hydrous lower alcohol, add concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid to 0.1N, or add trifluoroacetic acid to 0.5% to room temperature or By heating, the sugar linked to the 20th position of each ginsenoside is removed by a hydrolysis reaction, and at the same time, the hydroxyl group is removed by a dehydration reaction. The obtained reaction solution is extracted with ether, the extract is neutralized with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and then the solvent is distilled off under reduced pressure. The concentrate obtained by the above method a) or b) was subjected to silica gel column chromatography [for example, silica gel manufactured by Merck, 60-230 mesh; elution solvent: chloroform-ethyl acetate-ethanol (1: 1: 0.015)]. Then, the product is separated and purified to give quadipanaxadiol and quadipanaxatriol. Each of them is recrystallized in a mixed solvent such as methanol-water to give quazipanaxadiol and quazipanaxatriol.

In addition to the ginseng (Panax ginseng, CMA Mayer) described above, the guadipanaxadiol and quadipanaxatriol of the present invention contain ginsenoside Rb1 and Rd in a large amount. Panax Pseudoginseng, Warrich or Panax Notoginseng, Parkir) and American Carrot (Panax Kinki Yufolium, Linnaeus), and Ginsenoside Rb2-containing Tochibananjin (Panax japonica, CIA Mayer) and Himalaya Carrot (Panax) It can be obtained by the above-mentioned method using a Panax genus plant such as Pseudoginseng, Zubsubu or Himalayichius pal, Angstay Florius) as a raw material. Further, other plants containing a saponin having a 20 (S) -protopanaxadiol nucleus as a skeleton and having a similar sugar coordination (eg, Amachazul of the family Cucurbitaceae (Ginostemma pentafilrum makino and its related plants)) Can also be obtained by the above method.

Furthermore, the quazipanaxadiol and quadipanaxatriol of the present invention increase the sensitivity of cancer cells that have acquired multidrug resistance to an anticancer drug, and eliminate the multidrug resistance, thereby providing a chemotherapeutic effect of the anticancer drug. It is extremely useful as an enhancer that remarkably enhances

In this case, the cancer cells whose sensitivity to the anticancer agent is increased by the enhancer of the present invention are adenocarcinoma cells including adrenal gland, kidney, liver, and colon tissue, pancreatic cancer cells, carcinoma cells, and plastocysis. Certain chronic myelogenous leukemia cells, non-small cell lung cancer cells, neuroblastoma cells,
Pheochromocytoma cells, adult acute lymphocytic leukemia cells, nodular poorly differentiated lymphoma cells, breast cancer cells, and ovarian cancer cells.

Further, the anticancer agent which enhances the anticancer activity by the enhancer in the present invention includes vinca alkaloid, epipodophyllotoxin, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, Cortisine, cytochalasin B, emetine, maytansine, and amsacrine. More preferred are Vinca alkaloids,
Epipodophyllotoxin, anthracycline antibiotics, actinomycin D, and plicamycin.

The enhancer of the present invention is administered at the same time as the anticancer agent or at different times. In the latter case, the potentiator is administered sufficiently close in time to enhance the efficacy of the anticancer drug.

The dose of the enhancer in the present invention varies depending on the medical condition, but in the case of oral administration to adults, it may be administered once or several times a day in an amount of 1 to 50 mg / day / 60 kg body weight, preferably , 3 to 15 mg / day / 60 kg body weight.

The enhancer according to the present invention comprises the active ingredient of the present invention alone or the active ingredient and a solid or liquid excipient. The administration method and dosage form are usually powders, tablets, suspensions / emulsions, capsules, granules, troches, pills, liquids, liquors, syrups, and limonase agents. There is a shape. Also,
Injectable into the body in the form of injections, or externally in the form of ointments, plasters, solutions, powders, ships, suppositories, aerosols, poultices, soniments, lotions, enemas, and emulsions. It may be. As the solid or liquid excipient used here, those known in the art are used. However, it is desirable to formulate the active ingredient of the present invention in a single dose as described above.

To give some specific examples, as excipients in powders and other powders for internal use, lactose, crystalline cellulose, starch, dextrin, calcium phosphate, calcium carbonate, synthetic and natural aluminum silicate, magnesium oxide. , Dry aluminum hydroxide, magnesium stearate, sodium bicarbonate, etc., and in the case of powder for external use, zinc oxide, talc, starch, kaolin, boric acid powder, zinc stearate, magnesium stearate, magnesium carbonate, precipitated carbonic acid. calcium,
Examples thereof include bismuth subgallate and potassium aluminum sulfate powder. Examples of the excipient in the liquid agent include water, glycerin, propylene glycol, simple syrup, ethanol, fatty oil, ethylene glycol, polyethylene glycol, sorbitol and the like. Further, in the case of ointment, fat, fatty oil, lanolin, petrolatum,
Hydrophobic base or hydrophilic base (emulsion base, emulsion base, made by combining glycerin, beeswax, wax, paraffin, liquid paraffin, resin, higher alcohol, plastics, glycols, water, and a surfactant. Water-soluble bases and suspending bases) are used as excipients.

The following examples are provided to illustrate the present invention and should not be construed as limited thereby.

【Example】

Example 1 After shredding the above-ground part of Korean ginseng (made in Korea, 6 kg),
Methanol (56 L) was added, and the mixture was cold soaked for several weeks. A methanol extract was obtained by filtration, and the residue was freshly added with methanol (48
L) was added and cold extraction was performed. Do the same operation a total of 3 times,
The obtained methanol extracts were combined and the solvent was distilled off under reduced pressure to obtain a methanol extract (1.15 kg). This methanol extract (0.84 kg) was added to n-hexane and water (2: 1.2
L) and the aqueous layer was extracted with ether (1 L) and then n-butanol (2 L). The solvent of the n-butanol portion was distilled off under reduced pressure to obtain total ginsenoside (0.39 kg). Dissolve this total ginsenoside (5 g) in purified water (50 ml),
Crude hesperidinase (0.5 g) was added, and the mixture was stirred at 37 ° C for 24 hours. Furthermore, acetic acid (50 ml) was added to this reaction solution, and the temperature was 70 ° C.
Heated for 4 hours. The reaction mixture was diluted with water and washed with ether (50m
It was extracted with l × 2). The ether extract was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and then the solvent was distilled off under reduced pressure to obtain an extract (1.2 g), which was subjected to silica gel column chromatography [Merck silica gel, 60- 2
30 mesh, 100g; Elution solvent: chloroform-ethyl acetate-
Ethanol (10: 2: 0.07)], and reverse phase silica gel column chromatography (Merck silica gel RP-18,300).
g; elution solvent: 85-90% methanol) for separation and purification,
Crystallization from water-methanol yielded wadipanaxadiol (38 mg) and wadipanaxatriol (100 mg).

Example 2 Total ginsenoside (10 g) obtained in Example 1
Peptone-yeast extract medium (g / L, peptone, 10; yeast extract, 5; L-cysteine hydrochloride monohydrate, 0.5; sodium chloride, 6.8; potassium chloride, 0.4; calcium chloride, 0.2; magnesium sulfate , 0.094; Sodium monohydrogen phosphate, 0.06; Potassium dihydrogen phosphate, 0.06) (1000 ml), and added with human intestinal bacteria subcultured in a general medium for anaerobic bacteria (for example, GAM medium), Anaerobic culture was performed at 36 ° C for 48 hours. The reaction solution was diluted with water and extracted with ethyl acetate (200 ml). The ethyl acetate part was washed with water and the solvent was distilled off under reduced pressure to obtain an extract (1.9 g), which was dissolved in 50% aqueous acetic acid solution (100 ml).
Heated at ℃ for 4 hours. Dilute the reaction mixture with water and add ether (1
It was extracted with 00 ml x 2). The ether extract was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, then washed with water, and the extract obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography [Merck silica gel, 60-230 mesh, 200 g. Elution solvent: chloroform-ethyl acetate-ethanol (10: 2: 0.07)] and reverse phase silica gel column chromatography (Merck silica gel RP-18,300g; elution solvent: 85-90% methanol) for separation and purification And water-
Crystallized from methanol to give quazipanaxadiol (1.
0 g) and wadipanaxatriol (2.7 g) were obtained.

Example 3 An underground part of Panax ginseng (Korea, 2.7 kg) was shredded, 50% ethanol (5 L) was added, and the mixture was refluxed. An ethanol extract is obtained by filtration, and fresh ethanol (5 L) is added to the residue.
Was added and reflux extraction was performed. The same operation was performed 3 times in total, and the obtained ethanol extracts were combined and the solvent was distilled off under reduced pressure to obtain an ethanol extract (900 g). The ethanol extract (300 g) was dispersed in water (3 L), and the aqueous layer was extracted with acetic acid extract (0.5 L × 2). The aqueous layer part was replaced with ethyl acetate (2
L, 1L, 1L), and the water layer is a porous network cross-linked polystyrene resin adsorbent (Diaion)
HP-20, manufactured by Mitsubishi Kasei Co., Ltd.), wash the resin well with water, then elute with 50% methanol and methanol, and concentrate the methanol eluate to total ginsenoside (35
g) was obtained. This total ginsenoside (10 g) was dissolved in 0.1 N hydrochloric acid-ethanol (100 ml) and heated at 80 ° C for 2 hours. The ethanol of the reaction solution was distilled off under reduced pressure, diluted with water and extracted with ether (100 ml × 2). The ether extract was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and then the solvent was distilled off under reduced pressure to obtain an extract.
Silica gel column chromatography [Merck silica gel, 60-230 mesh, 200 g; elution solvent: chloroform-ethyl acetate-ethanol (10: 2: 0.07)], and reverse phase silica gel column chromatography (Merck silica gel RP
-18,300g; Elution solvent: 85-90% Methanol), isolate and purify, crystallize from water-methanol, and wadipanaxadiol (0.73g) and wadipanaxatriol (0.2
9g) was obtained.

Formulation Example 1 Lactose, crystalline cellulose, and magnesium stearate 1% were added to 30 mg of wadipanaxadiol or wadipanaxatriol and uniformly mixed, and the mixture was tableted using a tablet machine to give 1 tablet 200 mg. To obtain tablets.

Formulation Example 2 A sterilized vial was aseptically filled with an aqueous solution of 15 mg of wadipanaxadiol or quadipanaxatriol and polysorbate 80, and then water was removed to obtain an injection.

Formulation Example 3 Quazidipanaxadiol or quadipanaxatriol 15 mg, vinblastine sulfate 1 mg, and polysorbate 8
An aqueous solution of 0 was aseptically filled in a sterilized vial, and then water was removed to obtain an injection.

Example 4 In vitro in mouse leukemia cell line (P388) of enhancer
Cytotoxicity a) Test method Mouse leukemia cell line (P388) and its adriamycin (ADM) resistant cell line (P388 / ADM) were used for this test. This resistant cell line (P388 / ADM) was about 80 times more resistant to daunomycin (DAU) and about 180 times more resistant to vinblastine (VBL) than the parental cell line (P388). Resistant cell line (P
388 / ADM) (1 x 10 ⁶ ), enhancer (12.5-50 μM) and 2
The cells were cultured in a culture medium (20 μM mercaptoethanol, 10% fetal bovine serum-containing RPMI1640 medium) containing a double-diluted anticancer agent under steam-saturated 5% carbon dioxide for 48 hours. Separately from that, the same number of resistant cancer cells were cultured in a culture solution containing only the anticancer drug, and used as a control group. The number of each proliferative cancer cell was counted, and the 50% growth inhibitory concentration (IC ₅₀ ) of the anticancer agent was calculated. Then, the drug resistance index was calculated by the following formula. Drug resistance index (RF) = IC ₅₀ (P388 / ADM) / IC ₅₀ (P388) b) Test results The enhancers quadipanaxadiol and quadipanaxatriol are anticancer agents daunomycin (DAU) at concentrations that do not show cytotoxicity. The drug resistance index of the resistant cell line (P388 / ADM) against vinblastine and vinblastine (VBL) was significantly decreased as compared with verapamil used as a control drug, and as a result, the drug resistance of the resistant cell line was eliminated.

[Table 1] As can be seen from the above results, it is clear that the quazipanaxadiol and quadipanaxatriol of the present invention enhance the drug efficacy of anticancer agents and eliminate drug resistance, and therefore can be used as enhancers.

[0023]

INDUSTRIAL APPLICABILITY The quazipanaxadiol and quadipanaxatriol of the present invention increase the sensitivity of cancer cells that have acquired multidrug resistance to an anticancer drug, and eliminate the multidrug resistance, whereby the chemotherapeutic effect of the anticancer drug is improved. It is extremely useful as an enhancer that remarkably enhances

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomoyuki Matsumiya 8-13 shares, Shiraitodai, Fuchu-shi, Tokyo Inside the Happy World Ichito Life Science Research Institute (72) Inventor Masamori Uchiyama 3 Shiraitodai, Fuchu-shi, Tokyo 8 stock companies at 13-chome Happy World Ichito Life Science Research Center

Claims (4)

[Claims] 1. Formula (I): Damara-20 (22), 24-diene-3β, 12β-diol represented by 2. Formula (II): Damara represented by -20, (22), 24-diene-3β, 6α, 12β-
Triol. 3. Damara-20 (22), 24-diene-3β, 12β-diol represented by the formula (I) according to claim 1, or damara represented by the formula (II) according to claim 2. -20, (2
2) An enhancer for increasing the susceptibility of cancer to an anticancer drug containing, as an active ingredient, 24-diene-3β, 6α, 12β-triol. 4. 20 (S) -protopanaxadiol and 20
A glycoside having (S) -protopanaxatriol as a skeleton,
Damara-20 (22), 24-diene-3β, 12β-diol represented by formula (I) according to claim 1 obtained as sapogenin by hydrolysis and dehydration treatment, and formula according to claim 2. Damara represented by (II) -20, (22), 24-
A method for producing diene-3β, 6α, 12β-triol.